FIELD OF THE INVENTION
[0001] The present invention relates to a process for preparing quinazolin-4-one or its
derivatives from anthranilic acid or its derivatives or ammonium anthranilate or its
derivatives. The quinazolin-4-one and its derivatives are useful as intermediates
or starting compounds for preparing pharmaceutically active compounds or agricultural
chemicals.
BACKGROUND OF THE INVENTION
[0002] The following processes are known for preparing quinazolin-4-one or its derivatives
from anthranilic acid or its derivatives.
1) EP 1029853 discloses a process for preparing 6-iodoquinazolin-4-one by reacting
5-iodoanthranilic acid with formamidine acetate in ethanol for 20 hours. This process
has problems in that the reaction period is long, and it is necessary to use expensive
formamidine in an excessive amount.
2) Chem. Pharm. Bull., 46, 1926 (1998) describes a process for preparing quinazolin-4-one by reacting anthranilic
acid with formamide. This process has a problem in that teratogenetic formamide is
used in an excessive amount.
[0003] Thus, these processes have various problems, and hence are not satisfactory as industrially
employable processes for preparing quinazolin-4-one or its derivatives.
SUMMARY OF THE INVENTION
[0004] The present invention has an object to provide an industrially advantageous simple
process for preparing quinazolin-4-one or its derivatives from anthranilic acid or
its derivatives or ammonium anthranilate or its derivatives in high yields under moderate
conditions.
[0005] The present invention resides in a process for preparing quinazolin-4-one or a derivative
thereof having the formula (2):
in which each of R
1, R
2, R
3 and R
4 independently represents a hydrogen atom, a halogen atom, or a group that does not
participate in the following reaction and may have a substituent, or R
1, R
2, R
3 and R
4 may be combined to form a ring,
which is characterized in that an anthranilic acid or a derivative thereof having
the formula (1):
in which each of R
1, R
2, R
3 and R
4 has the same meaning as above,
is reacted with formic acid or a derivative thereof in the presence of ammonia.
[0006] The invention further relates to a process for preparing quinazolin-4-one or a derivative
thereof having the above-mentioned formula (2) which is characterized in that ammonium
anthranilate or a derivative thereof having the formula (3):
in which each of R
1, R
2, R
3 and R
4 independently represents a hydrogen atom, a halogen atom, or a group that does not
participate in the following reaction and may have a substituent, or R
1, R
2, R
3 and R
4 may be combined to form a ring,
is reacted with formic acid or a derivative thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0007] The anthranilic acid or a derivative thereof employed in the invention is represented
by the above-mentioned formula (1). In the formula (1), each of R
1, R
2, R
3 and R
4 is the same or different and is a hydrogen atom, a halogen atom, or a group that
does not participate in the reaction and may have a substituent. In more detail, each
is hydrogen, alkyl, cycloalkyl, aralkyl, aryl, halogen, hydroxyl, alkoxy, alkylthio,
nitro, cyano, carbonyl, or amino(not for R
1). Otherwise, R
1, R
2, R
3 and R
4 may be combined to form a ring. The alkyl contained in these groups preferably has
1 to 12 carbon atoms.
[0008] Examples of the alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl,
heptyl, octyl, nonyl, and decyl. These groups can be any of isomers. Examples of the
cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
and cyclooctyl. Examples of the aralkyl groups include benzyl, phenethyl, and phenylpropyl.
These groups can be any of isomers. Examples of the aryl groups include phenyl, p-tolyl,
naphthyl, and anthranyl. These groups can be any of isomers. Examples of halogen atoms
include fluorine, chlorine, bromine, and iodine. Examples of the alkoxy groups include
methoxy, ethoxy, and propoxy. These groups can be any of isomers. Examples of the
alkylthio groups include methylthio, ethylthio, and propylthio. These groups can be
any of isomers.
[0009] The above-mentioned alkyl, cycloalkyl, aralkyl, aryl, alkoxy, alkylthio, and amino(not
for R
1) may have a substituent. Examples of the substituents include a substituent bonded
via a carbon atom, a substituent bonded via an oxygen atom, a substituent bonded via
a nitrogen atom, a substituent bonded via a sulfur atom, and a halogen atom.
[0010] Examples of the substituents bonded via a carbon atom include alkyl groups such as
methyl, ethyl, propyl, butyl, pentyl, and hexyl; cycloalkyl groups such as cyclopropyl,
cyclobutyl, cyclopentyl, and cyclohexyl; alkenyl groups such as vinyl, allyl, propenyl,
cyclopropenyl, cyclobutenyl, and cyclopentenyl; heterocyclic alkenyl groups such as
pyrrolidinyl, pyrrolyl, furyl, and thienyl; aryl groups such as phenyl, tolyl, xylyl,
biphenylyl, naphthyl, anthryl, and phenanthoryl; acyl groups (may be acetallized)
such as formyl, acetyl, propionyl, acryloyl, pivaloyl, cyclohexylcarbonyl, benzoyl,
naphthoyl, and toluoyl; carboxyl groups; alkoxycarbonyl groups such as methoxycarbonyl
and ethoxycarbonyl; aryloxycarbonyl groups such as phenoxycarbonyl; halogenated alkyl
groups such as trifluoromethyl; and cyano group. These groups can be any of isomers.
[0011] Examples of the substituents bonded via an oxygen atom include hydroxyl; alkoxy groups
such as methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, and benzyloxy;
and aryloxy groups such as phenoxy, toluyloxy, and naphthyloxy. These groups can be
any of isomers.
[0012] Examples of the substituents bonded via a nitrogen atom include primary amino groups
such as methylamino, ethylamino, butylamino, cyclohexylamino, phenylamino, and naphthylamino;
secondary amino groups such as dimethylamino, diethylamino, dibutylamino, methylethylamino,
methylbutylamino, and diphenylamino; heterocyclic amino groups such as morpholino,
piperidino, piperazinyl, pyrazolidinyl, pyrrolidino, and indolyl; and imino group.
These groups can be any of isomers.
[0013] Examples of the substituents bonded via a sulfur atom include mercapto; thioalkoxy
groups such as thiomethoxy, thioethoxy, and thiopropoxy; and thioaryloxy groups such
as thiophenoxy, thiotoluyloxy, and thionaphthyloxy. These groups can be any of isomers.
[0014] Examples of the halogen atoms include fluorine, chlorine, bromine, and iodine.
[0015] The ammonium anthranilate and its derivatives employable in the invention are represented
by the aforementioned formula (3). R
1, R
2, R
3 and R
4 seen in the formula (3) have the same meanings as described hereinbefore.
[0016] Examples of the formic acid and its derivatives include formic acid; formic acid
esters such as methyl formate and ethyl formate; and orthoformic acid esters such
as methyl orthoformate and ethyl orthoformate. Preferred are formic acid esters and
orthoformic acid esters. More preferred are orthoformic acid esters. Specifically
preferred are methyl orthoformate and ethyl orthoformate.
[0017] The formic acid or its derivatives can be preferably employed in an amount of 1.0
to 10 moles, more preferably 1.1 to 3.0 moles, per one mole of anthranilic acid or
its derivatives or ammonium anthranilate or its derivatives.
[0018] The ammonia employed in the reaction can be liquid ammonia or gaseous ammonia. Preferred
is a solution of ammonia in an organic solvent such as alcohol (e.g., methanol) and
ether (e.g., dioxane). In the latter case, the ammonia solution is of a concentration
of, preferably, 1 to 90 wt.%, more preferably 3 to 30 wt.%. The ammonia is preferably
employed in an amount of 1 to 60 moles, more preferably 2 to 20 moles, per one mole
of anthranilic acid or its derivative.
[0019] The reaction of the invention can be conducted in the presence or absence of a solvent.
There are no limitation with respect to the solvents employed in the reaction, provided
that the solvents do not disturb the reaction. Examples are alcohols such as methanol,
ethanol, isopropyl alcohol, n-butyl alcohol, and t-butyl alcohol; amides such as N,N-dimethylformamide
and N-methylpyrrolidone; ureas such as N,N'-dimethylimidazolidinone; sulfoxides such
as dimethyl sulfoxide; aromatic hydrocarbons such as benzene, toluene, xylene, and
mesitylene; halogenated aliphatic hydrocarbons such as methylene chloride, chloroform,
and dichloroethane; nitriles such as acetonitrile and propionitrile; and ethers such
as diethyl ether, tetrahydrofuran, and dioxane. Preferred are alcohols. More preferred
are methanol and ethanol. These solvents can be employed singly or in combination.
[0020] The amount of the solvent employed in the reaction depends on the homogeneity and
stirring condition of the reaction mixture. It is preferred that the solvent is employed
in an amount of 0 to 50 g (more preferably 0 to 20 g, most preferably 0 to 5 g) per
one gram of the anthranilic acid or its derivative or ammonium anthranilate or its
derivative.
[0021] The reaction of the invention can be performed, for instance, by mixing and stirring
the compounds to be involved in the invention. The reaction is preferably performed
at a temperature of 40 to 200°C, more preferably 50 to 150°C. There is no limitation
with respect to the pressure for the reaction.
[0022] After the reaction is complete, the final product, i.e., quinazolin-4-one or its
derivative, can be isolated and purified by the conventional procedures such as concentration,
distillation, recrystallization, and column chromatography.
[0023] The invention is further described by the following examples.
[Example 1] --- Preparation of quinazolin-4-one
[0024] In a 2-mL volume stainless steel pressure-resistant vessel were placed 260 mg (1.9
mmol) of anthranilic acid, 403 mg (3.8 mmol) of methyl orthoformate, and 1.2 mL (8.4
mmol) of 15 wt.% ammonia methanol solution. The reaction was carried out at 120°C
for 2 hours. After the reaction was complete, the reaction mixture was cooled to room
temperature and analyzed (according to absolute quantitative analysis) by high performance
liquid chromatography. There was produced 278 mg (reaction yield: 100%) of quinazolin-4-one.
[Example 2] --- Preparation of 7-chloroquinazolin-4-one
[0025] In a 2-mL volume stainless steel pressure-resistant vessel were placed 330 mg (1.9
mmol) of 4-chloroanthranilic acid, 403 mg (3.8 mmol) of methyl orthoformate, and 1.2
mL (8.4 mmol) of 15 wt.% ammonia methanol solution. The reaction was carried out at
120°C for 2 hours. After the reaction was complete, the reaction mixture was cooled
to room temperature and analyzed (according to absolute quantitative analysis) by
high performance liquid chromatography. There was produced 343 mg (reaction yield:
99%) of 7-chloroquinazolin-4-one.
[Example 3] --- Preparation of 6-iodoquinazolin-4-one
[0026] In a 2-mL volume stainless steel pressure-resistant vessel were placed 500 mg (1.9
mmol) of 5-iodoanthranilic acid, 403 mg (3.8 mmol) of methyl orthoformate, and 1.2
mL (8.4 mmol) of 15 wt.% ammonia methanol solution. The reaction was carried out at
120°C for 2 hours. After the reaction was complete, the reaction mixture was cooled
to room temperature and analyzed (according to absolute quantitative analysis) by
high performance liquid chromatography. There was produced 515 mg (reaction yield:
99%) of 6-iodoquinazolin-4-one.
[Example 4] --- Preparation of 6-iodoquinazolin-4-one
[0027] The procedures of Example 3 were repeated except that the reaction temperature and
reaction period were changed to 95°C and 4 hours, respectively. There was produced
485 mg (reaction yield: 93%) of 6-iodoquinazolin-4-one.
[Example 5] --- Preparation of 6-iodoquinazolin-4-one
[0028] The procedures of Example 3 were repeated except that the amount of methyl orthoformate
was changed to 320 mg (3.0 mmol). There was produced 514 mg (reaction yield: 99%)
of 6-iodoquinazolin-4-one.
[Example 6] --- Preparation of 6-iodoquinazolin-4-one
[0029] In a 200 mL volume stainless steel pressure-resistant vessel equipped with a thermometer,
an pressure gauge, and a stirrer were placed 25.0 g (95 mmol) of 5-iodoanthranilic
acid, 17.1 g (162 mmol) of methyl orthoformate, and 50 mL (349 mmol) of 15 wt.% ammonia
methanol solution. The reaction was carried out at a temperature of 100-110°C and
a pressure of 0.5 MPa (gauge pressure) for 8 hours. After the reaction was complete,
the reaction mixture was cooled to a temperature of 0-10°C and placed under reduced
pressure to distill ammonia off. The residual reaction mixture was then stirred at
0°C for one hour. The precipitated solid was collected by filtration and dried, to
obtain 24.3 g (isolated yield: 94%) of 6-iodoquinazolin-4-one as a pale gray crystalline
product.
[Example 7] --- Preparation of 6-iodoquinazolin-4-one
[0030] In a 2-mL volume stainless steel pressure-resistant vessel were placed 500 mg (1.9
mmol) of 5-iodoanthranilic acid, 342 mg (5.7 mmol) of methyl formate, and 1.2 mL (8.4
mmol) of 15 wt.% ammonia methanol solution. The reaction was carried out at 150°C
for 4 hours. After the reaction was complete, the reaction mixture was cooled to room
temperature and analyzed (according to absolute quantitative analysis) by high performance
liquid chromatography. There was produced 401 mg (reaction yield: 77%) of 6-iodoquinazolin-4-one.
[Example 8] --- Preparation of 6-iodoquinazolin-4-one
[0031] The procedures of Example 7 were repeated except that methyl formate was changed
to 263 mg (5.7 mmol) of formic acid. There was produced 302 mg (reaction yield: 58%)
of 6-iodoquinazolin-4-one.
[Reference Example 1] --- Preparation of ammonium anthranilate
[0032] In a 50 mL volume glass vessel equipped with a stirrer and a thermometer were placed
5.0 g (36.5 mmol) of anthranilic acid and 20 mL (156 mmol) of 15 wt.% ammonia methanol
solution. The reaction was carried out for 2 hours at room temperature. After the
reaction was complete, the reaction mixture was concentrated under reduced pressure,
to obtain 5.0 g (isolated yield: 94%) of ammonium anthranilate as white solid.
[0033] The physical characteristics of the ammonium anthranilate were described below.
1H-NMR (DMSO-d
6, δ (ppm)): 6.37-6.43 (1H, m), 6.56 (1H, dd, J=1.2, 8.1Hz), 6.95 (6H, brs), 6.98-7.04
(1H, m), 7.69-7.72 (1H, dd, J=1.8, 7.8Hz).
[Example 9 --- Preparation of quinazolin-4-one
[0034] In a 2-mL volume stainless steel pressure-resistant vessel were placed 280 mg (1.8
mmol) of ammonium anthranilate (prepared in the same manner as in Reference Example
1), 400 mg (3.6 mmol) of methyl orthoformate, and 1.5 mL of methanol. The reaction
was carried out at 120°C for 2 hours. After the reaction was complete, the reaction
mixture was cooled to room temperature and analyzed (according to absolute quantitative
analysis) by high performance liquid chromatography. There was produced 214 mg (reaction
yield: 81%) of quinazolin-4-one.
[Reference Example 2] --- Preparation of ammonium 4-chloroanthranilate
[0035] In a 50 mL volume glass vessel equipped with a stirrer and a thermometer were placed
5.0 g (29.1 mmol) of 4-chloroanthranilic acid and 20 mL (156 mmol) of 15 wt.% ammonia
methanol solution. The reaction was carried out for 2 hours at room temperature. After
the reaction was complete, the reaction mixture was concentrated under reduced pressure,
to obtain 5.0 g (isolated yield: 95%) of ammonium 4-chloroanthranilate as white solid.
[0036] The physical characteristics of the ammonium 4-chloroanthranilate (which was a new
compound) were described below.
1H-NMR (DMSO-d
6, δ (ppm)): 6.43 (1H, dd, J=2.4, 8.4Hz), 6.69 (1H, d, J=2.4Hz), 7.0 (3H, brs), 7.69
(1H, d, J=8.4Hz), 11.0 (3H, brs).
[Example 10 --- Preparation of 7-chloroquinazolin-4-one
[0037] In a 2-mL volume stainless steel pressure-resistant vessel were placed 340 mg (1.8
mmol) of ammonium 4-chloroanthranilate (prepared in the same manner as in Reference
Example 2), 400 mg (3.6 mmol) of methyl orthoformate, and 1.5 mL of methanol. The
reaction was carried out at 120°C for 2 hours. After the reaction was complete, the
reaction mixture was cooled to room temperature and analyzed (according to absolute
quantitative analysis) by high performance liquid chromatography. There was produced
176 mg (reaction yield: 54%) of 7-chloroquinazolin-4-one.
[Reference Example 3] --- Preparation of ammonium 5-chloroanthranilate
[0038] In a 50 mL volume glass vessel equipped with a stirrer and a thermometer were placed
5.0 g (29.1 mmol) of 5-chloroanthranilic acid and 20 mL (156 mmol) of 15 wt.% ammonia
methanol solution. The reaction was carried out for 2 hours at room temperature. After
the reaction was complete, the reaction mixture was concentrated under reduced pressure,
to obtain 5.0 g (isolated yield: 95%) of ammonium 5-chloroanthranilate as pale yellow
solid.
[0039] The physical characteristics of the ammonium 5-chloroanthranilate (which was a new
compound) were described below.
1H-NMR (DMSO-d
6, δ (ppm)): 6.57 (1H, d, J=8.4Hz), 6.99 (1H, dd, J=2.7, 8.4Hz), 7.0 (3H, brs), 7.65
(1H, d, J=2.7Hz), 11.0 (3H, brs).
[Example 11 --- Preparation of 6-chloroquinazolin-4-one
[0040] In a 2-mL volume stainless steel pressure-resistant vessel were placed 340 mg (1.8
mmol) of ammonium 5-chloroanthranilate (prepared in the same manner as in Reference
Example 3), 400 mg (3.6 mmol) of methyl orthoformate, and 1.5 mL of methanol. The
reaction was carried out at 120°C for 2 hours. After the reaction was complete, the
reaction mixture was cooled to room temperature and analyzed (according to absolute
quantitative analysis) by high performance liquid chromatography. There was produced
307 mg (reaction yield: 94%) of 6-chloroquinazolin-4-one.
[Example 12 --- Preparation of 6-chloroquinazolin-4-one
[0041] In a 2-mL volume stainless steel pressure-resistant vessel were placed 340 mg (1.8
mmol) of ammonium 5-chloroanthranilate (prepared in the same manner as in Reference
Example 3), 400 mg (3.6 mmol) of methyl orthoformate, and 1.5 mL of acetonitrile.
The reaction was carried out at 120°C for 2 hours. After the reaction was complete,
the reaction mixture was cooled to room temperature and analyzed (according to absolute
quantitative analysis) by high performance liquid chromatography. There was produced
303 mg (reaction yield: 93%) of 6-chloroquinazolin-4-one.
[Reference Example 4] --- Preparation of ammonium 5-iodoanthranilate
[0042] In a 200 mL volume glass vessel equipped with a stirrer and a thermometer were placed
10.0 g (38 mmol) of 5-iodoanthranilic acid and 100 mL (780 mmol) of 15 wt.% ammonia
methanol solution. The reaction was carried out for 3 hours at room temperature. After
the reaction was complete, the reaction mixture was concentrated under reduced pressure,
to obtain 9.0 g (isolated yield: 85%) of ammonium 5-iodoanthranilate as pale red solid.
[0043] The physical characteristics of the ammonium 5-iodoanthranilate (which was a new
compound) were described below.
1H-NMR (DMSO-d
6, δ (ppm)): 6.45 (1H, d, J=8.7Hz), 6.5 (3H, brs), 7.25 (1H, dd, J=2.4, 8.7Hz), 7.96
(1H, d, J=2.4Hz), 11.0 (3H, brs).
[Example 13 --- Preparation of 6-iodoquinazolin-4-one
[0044] In a 2-mL volume stainless steel pressure-resistant vessel were placed 530 mg (1.9
mmol) of ammonium 5-iodoanthranilate (prepared in the same manner as in Reference
Example 4), 403 mg (3.8 mmol) of methyl orthoformate, and 1.5 mL of methanol. The
reaction was carried out at 120°C for 2 hours. After the reaction was complete, the
reaction mixture was cooled to room temperature and analyzed (according to absolute
quantitative analysis) by high performance liquid chromatography. There was produced
402 mg (reaction yield: 77%) of 6-iodoquinazolin-4-one.
[Example 14 --- Preparation of 6-iodoquinazolin-4-one
[0045] In a 2-mL volume glass vessel equipped with a reflux condenser were placed 530 mg
(1.9 mmol) of ammonium 5-iodoanthranilate (prepared in the same manner as in Reference
Example 4), 403 mg (3.8 mmol) of methyl orthoformate, and 1.5 mL of n-butyl alcohol.
The reaction was carried out at 120°C for 2 hours. After the reaction was complete,
the reaction mixture was cooled to room temperature and analyzed (according to absolute
quantitative analysis) by high performance liquid chromatography. There was produced
350 mg (reaction yield: 67%) of 6-iodoquinazolin-4-one.
UTILIZATION IN INDUSTRY
[0046] According to the invention, quinazolin-4-one or its derivative can be prepared from
anthranilic acid or its derivatives or ammonium anthranilate or its derivative in
a high yield under moderate conditions by simple procedures.
1. A process for preparing quinazolin-4-one or a derivative thereof having the formula
(2):
in which each of R
1, R
2, R
3 and R
4 independently represents a hydrogen atom, a halogen atom, or a group that does not
participate in the following reaction and may have a substituent, or R
1, R
2, R
3 and R
4 may be combined to form a ring,
which is
characterized in that an anthranilic acid or a derivative thereof having the formula (1):
in which each of R
1, R
2, R
3 and R
4 has the same meaning as above,
is reacted with formic acid or a derivative thereof in the presence of ammonia.
2. The process for preparing quinazolin-4-one or a derivative thereof according to claim
1, wherein the anthranilic acid or a derivative thereof is reacted with an orthoformic
acid ester.
3. The process for preparing quinazolin-4-one or a derivative thereof according to claim
1, wherein each of R1, R2, R3 and R4 independently is a hydrogen atom or a halogen atom.
4. The process for preparing quinazolin-4-one or a derivative thereof according to claim
1, wherein each of R1, R2, R3 and R4 independently is a hydrogen atom, a halogen atom, or a group selected from the group
consisting of alkyl, cycloalkyl, aralkyl, aryl, hydroxyl, alkoxy, alkylthio, nitro,
cyano, carbonyl, and amino, provided that R1 is not amino.
5. A process for preparing quinazolin-4-one or a derivative thereof having the formula
(2):
in which each of R
1, R
2, R
3 and R
4 independently represents a hydrogen atom, a halogen atom, or a group that does not
participate in the following reaction and may have a substituent, or R
1, R
2, R
3 and R
4 may be combined to form a ring,
which is
characterized in that ammonium anthranilate or a derivative thereof having the formula (3):
in which each of R
1, R
2, R
3 and R
4 has the same meaning as above,
is reacted with formic acid or a derivative thereof.
6. The process for preparing quinazolin-4-one or a derivative thereof according to claim
5, wherein the ammonium anthranilate or a derivative thereof is reacted with an orthoformic
acid ester.
7. The process for preparing quinazolin-4-one or a derivative thereof according to claim
5, wherein each of R1, R2, R3 and R4 independently is a hydrogen atom or a halogen atom.
8. The process for preparing quinazolin-4-one or a derivative thereof according to claim
5, wherein each of R1, R2, R3 and R4 independently is a hydrogen atom, a halogen atom, or a group selected from the group
consisting of alkyl, cycloalkyl, aralkyl, aryl, hydroxyl, alkoxy, alkylthio, nitro,
cyano, carbonyl, and amino, provided that R1 is not amino.
9. Ammonium anthranilate or a derivative thereof having the formula (3):
wherein each of R
1, R
2, R
3 and R
4 independently is a hydrogen atom, a halogen atom, or a group selected from the group
consisting of alkyl, cycloalkyl, aralkyl, aryl, hydroxyl, alkoxy, alkylthio, nitro,
cyano, carbonyl, and amino, provided that R
1 is not amino, and that there is no case that all of R
1, R
2, Rand R
4 are hydrogen.